Fast-melt tablet and method of making same

ABSTRACT

Provided is an improved, fast-melting solid dosage form which readily disintegrates when placed in the mouth. The solid dosage form preferably being a tablet comprising the following primary ingredients whose proportions are calculated as weight percent on the total weight of the tablet: (a) from about 30 to 50 weight percent, of a pharmaceutically acceptable active ingredient component; (b) an effervescent couple consisting of about 2 to 5 weight percent of an effervescence base about 2 to 5 weight percent of an effervescence acid suitable for achieving a gas evolving reaction with the effervescence base upon being contacted with an aqueous solution such as saliva; (c) about 35 to 50 weight percent of a pharmaceutically acceptable starch as a bulking and disintegrating agent; (d) about 0.04 to 1 weight percent of a starch degrading enzyme; and (e) about 2 to 5 weight percent of a tablet lubricant. Additionally, the tablet may comprise flavoring agents. The tablet is formed of granules of a mixture of the active ingredient component, the effervescence base, and the starch, admixed to a powderous blend of the remaining ingredients, subsequently compressed in tablet form. Also provided is a method of making the solid dosage form of the present invention.

REFERENCE TO OTHER APPLICATIONS

This application is a continuation-in-part of application Ser. No.08/562,057, filed Nov. 22, 1995.

BACKGROUND OF THE INVENTION

1. Field Of The Invention

The invention relates to the field of solid dosage forms for ingestionof active substances which are absorbed in the mouth or digestive tract.More specifically, the invention is concerned with solid, effervescentand "fast-melting" tablets. Most particularly, the invention isconcerned with tablet formulations comprising one or more activesubstances, an effervescent couple such as sodium bicarbonate and malicacid, a swelling and disintegrating agent and an enzyme acting as adisintegration regulating agent hereinafter termed disintegrationmodulator. In one embodiment, the active substances may be antacids suchas calcium carbonate and magnesium hydroxide.

2. Description Of The Prior Art

The use of compressed tablet compositions is well known for oraladministration of various active substances such as antacids. The use ofantacids such as calcium carbonate and magnesium hydroxide to treatgastric hyperacidity is also well known.

Also known is the use of sodium bicarbonate and malic acid as aneffervescent couple which, when contacted with saliva or other aqueoussolutions, undergoes an effervescent reaction.

The use of bulking and disintegrating agents such as sugars, polyhydricalcohols, e.g. mannitol, sorbitol and xylitol and starches is alsoknown.

Solid dosage forms destined for ingestion, including antacidformulations, have been prepared and marketed in various forms such astablets, lozenges and powders. Many solid formulations do not readilydisintegrate in the mouth and impart a chalky taste.

Canadian Patent No. 1,258,428, Damini et al., provides a soft candyantacid composition comprising about 5-50 weight percent of antacidingredient, about 50-95 weight percent of a confectionary base (fondant)and a plasticizer to avoid crystallization of the sugars contained inthe confectionary base. When placed in the mouth, the soft candy willgradually liquefy to release the antacid ingredients while masking theirtaste.

U.S. Pat No. 5,178,878 and 5,223,264, to Wehling et al. disclosecompressed tablet compositions comprising an effervescent coupledisintegration agent, an effective amount of active ingredient such asan antacid, and a non-effervescent disintegrant such as starch in aproportion up to 20 weight percent and preferably 2 to 10 weight percentof composition (U.S. Pat. No. 5,223,264, column 6, lines 62-64, and U.S.Pat. No. 5,178,878, column 7, lines 48-51,). When orally ingested, thetablets are said to dissolve in the mouth in less than 10 minutes anddesirably between 7 minutes and 30 seconds.

U.S. Pat. No. 4,369,308, Trubiano, discloses the use of variouslow-swelling starches as tablet disintegrants. The starches are said tobe useful in many tableting methods in amounts of about 10 weightpercent or less.

It is apparent that starches, when used as tablet swelling anddisintegrating agents are typically present in a proportion of onlyabout 20 weight percent or less and nothing is added to the starches tocause a rapid degradation of the starches thereby assisting the faster"melting" of the tablet.

Thus, there remains a need for an improved solid dosage form which notonly stores well and does not easily chip or break during handling butalso very quickly dissolves in the mouth, i.e. in less than 30 seconds,preferably less than about 20 seconds, and which imparts a pleasantmouth feel, a palatable taste and freshens breath.

SUMMARY OF THE INVENTION

This invention is the result of a project whose goal was the developmentof an improved solid dosage form which upon ingestion would immediately"melt" in the mouth and disintegrate in a few seconds. Corollaryobjectives were to provide solid formulations which would store well,would not collapse or fragment during shipping and handling of theproduct, and yet when placed in the mouth would immediately disintegratewith a good mouth feel with no apparent aftertaste and at the same timefreshen breath.

It was surprisingly discovered that those goals and objectives could beachieved by using a starch as a bulking and disintegrating agent and, atthe same time, an effervescent couple as a supplemental disintegratingagent and a starch degrading enzyme as a disintegration modulator. Thus,an important synergistic effect of very rapid tablet dissolution inaqueous environments is observed when using a starch together with aneffervescent couple and a starch degrading enzyme. In a preferredembodiment, a large proportion of starch is used, i.e. in the order of35 to 50 percent by weight.

Accordingly, the invention provides, in one aspect, a fast-melting soliddosage form, preferably an antacid tablet, which will readilydisintegrate when placed in the mouth, said solid dosage form comprisingthe following primary ingredients:

(a) a therapeutically effective amount of a pharmaceutically acceptableactive ingredient component;

(b) an effervescent couple consisting of an effervescence base and aneffervescence acid suitable for achieving a gas evolving reaction withsaid effervescence based upon said effervescent couple being contactedwith an aqueous solution;

(c) a bulking and disintegrating agent consisting of starch;

(d) at least one starch degrading enzyme suitable for achieving a starchdegradation reaction upon said solid dosage form being contacted with anaqueous solution;

(e) a solid dosage form lubricant.

In a preferred embodiment, the primary ingredients will be present inthe following proportions expressed as weight percentages:

(a) about 25 to 50 weight percent, of the pharmaceutically acceptableactive ingredient;

(b) about 3 to 5 weight percent of the effervescence base and about 3 to5 weight percent of the effervescence acid;

(c) about 35 to 50 weight percent of the pharmaceutically acceptablestarch;

(d) about 0.04 to 2 weight percent of the starch-degrading enzyme;

(e) about 2 to 5 weight percent of the lubricant.

In a further aspect, the invention provides a method of making the solidformulations of the present invention. The method can be summarized ascomprising the steps of:

(a) sieving to powder and mixing the primary internal phase ingredients,comprising the active ingredient component, the starch and theeffervescence base to obtain an internal phase mixture;

(b) wet granulating said mixture to obtain small granules;

(c) sieving said granules to a generally uniform size distribution ofsaid granules;

(d) mixing said granules with the external phase primary ingredientscomprising the effervescence acid, the starch degrading enzyme and thesolid dosage form lubricant;

(e) compressing the resulting mixture in a compression device,preferably a tablet press, to obtain a porous and fast-melting tablet.

Other objects and further scope of applicability of the presentinvention will become apparent from the detailed description givenhereinafter. It should be understood, however, that this detaileddescription, while indicating preferred embodiments of the invention, isgiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art.

BREIF DESCRIPTION OF THE DRAWINGS

The invention will be further explained and elucidated in the followingdescription referring to both method and apparatus, with reference tothe accompanying drawings, in which:

FIG. 1 represents a known kind of EIT applied to material contained in acircular-section vessel or pipeline of which the containing wall is ofelectrically non- conductive material;

FIG. 2 represents an application of EIT in accordance with the inventionto material contained in a circular-section vessel or pipeline of whichthe containing wall is of electrically conductive material such as ametal;

FIG. 3 is a schematic sectional view of one of a plurality of similarelectrodes mounted in the electrically conductive containing wall shownin FIG. 2 but electrically insulated from the wall and from each other;

FIG. 4 represents the electrical potentials which, when a givenelectrical potential or current is applied to one of the electrodesshown in FIG. 2, may be measured at the other such electrodes;

FIG. 5 is a representation of pixel sensitivity coefficients as used inimplementing an image reconstruction in accordance with the invention;

FIG. 6 is a reconstructed image of three glass rods dipping into watercontained in a metal-walled vessel;

FIG. 7 represents an electrically non-conductive vessel wall fitted witha plurality of electrodes and illustrates a suitable arrangement ofelectrode connections for use in carrying out the invention; and

FIG. 8, similar to FIG. 7, illustrates another suitable arrangement ofelectrode connections for use in carrying out the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A solid dosage form according to a preferred embodiment of the presentinvention is a compressed tablet suitable for ingestion. The expression"pharmaceutical active ingredient" as used in this disclosure means adrug, vitamin or mineral. Drugs may include, without limitation,antacids, antibiotics, antiseptics, antiulcerative agents, analgesics,antihistamines, antivirals, antiparasitic drugs, laxatives,gastro-intestinal motility modifying agents, antinauseants,antihyperlipidaemic agents, anti-inflammatories, antidiuretics,antiflatulents, tranquillizers, stimulants, sedatives,antihypertensives, anticonvulsants, antiepileptics, oncologic therapy,decongestants, antiasthmatics, betablockers and combinations thereof. Ina most preferred embodiment, the pharmaceutical active ingredientcomprised in the solid dosage form is an antacid or a mixture ofantacids. However, the present invention is not intended to be strictlylimited to antacids as active ingredients.

Hence, in a most preferred and illustrative embodiment, thepharmaceutical active ingredient is an antacid or a mixture of antacids.Examples of antacids are calcium carbonate, magnesium carbonate,magnesium hydroxide, magnesium oxide, aluminum hydroxide, bismuthsubsalicyclate, aluminum-magnesium hydroxide, and combinations thereof.

Preferably, the solid antacid formulation will comprise about 25 to 50weight percent of antacid powder, based on the weight of the solidantacid formulation. Most preferably, the formulation will compriseabout 20 to 30 weight percent of calcium carbonate and about 5 to 20weight percent of magnesium hydroxide.

The effervescent couple will comprise two dry ingredients which, whencontacted with aqueous solutions, will undergo an effervescent reaction.Effervescence relates to the generation and release of gas bubblesduring the effervescent reaction. In an effervescent couple, there isusually an effervescence base and an effervescence acid. Representativeof an effervescence base are: sodium carbonate, sodium bicarbonate,potassium carbonate, potassium bicarbonate, and calcium carbonate.Representative of an effervescence acid are: malic acid, maleic acid,tartaric acid, citric acid and alginic acid. Preferably, theeffervescence base will be sodium bicarbonate and the effervescence acidwill be malic acid.

Preferably, the solid antacid formulation will comprise about 3 to 5weight percent, of the effervescence base, and about 3 to 5 weightpercent of the effervescence acid. However, it is noted that a portionof the antacid active ingredient, for example calcium carbonate, mayalso contribute to the effervescence base.

The bulking and disintegrating agent will consist of starches,preferably corn starch, or modified starches, preferably sodium starchglycolate (Explotab®) or mixtures thereof, in any proportions. Thus,throughout this patent application, the word starch is used in a generalsense as encompassing various starches and modified starches. Preferablythe starch will be present in a proportion of about at least 40 weightpercent, and most preferably, at least 45 weight percent. The starchwill of course be pharmaceutically acceptable and should contribute tothe palatability of the formulation. Another advantage conferred by thehigh proportion of starch in the antacid tablet formulation is theincreased salivation effect when the tablet is placed in the mouth. Thisincreased salivation is induced by the porous nature of the starch.Increased salivation favors rapid ingestion of the active ingredientsand rapid disintegration of the tablet. The porosity of the starch baseallows a rapid penetration of saliva thereby assisting in the"fast-melting" of the tablet.

Furthermore, the starch degrading enzymes will have a synergistic effecton the "fast-melting" of the tablet. Indeed, the enzymes upon beingcontacted with an aqueous solution will immediately begin to convert thestarch to mono and polysaccharides which quickly dissolve in the aqueousenvironment and further contribute to improving the taste of the tabletand increasing salivation. Mouth dryness is also reduced because of thesoluble nature of the enzyme degradation products, which allows for afaster removal from the ingestion site by dissolution.

It is of course to be understood that enzymes will be chosen for theirdegradation effect on the starch and also for their stability over time,i.e. during the shelf-life of the tablet. Advantageously, the enzymewill be chosen from the group of starch degrading enzymes comprisingα-amylase, β-amylase, amyloglucosidase, debranching enzymes andglucose-fructose isomerase. Most preferably, the enzymes will be anequal mixture of amyloglucosidase and a-amylase. For example, a mixtureof equal weights of Novo Nordisk Biochem North America Inc.'sFungamyl/2500 BG™(α-amylase from Aspergillus oryzae, 1830/AF 13146,ID#110530 (Enzyme 1) and amyloglucosidase (AMG), Sample/AM20037,ID#110530 (Enzyme 2), were found to be adequate.

In accordance with the present invention, the "fast-melting" willreadily occur within a matter of seconds, typically within about 20seconds.

The solid effervescent formulation may have incorporated thereinoptional ingredients in order to confer it more desirable properties.Representative optional ingredients include: flavoring, aroma and breathfreshening agents such as peppermint oil and peppermint aroma, andnatural or artificial sweeteners such as aspartame. The selection ofsuch optional ingredients and their proportions is well within thoseskilled in the art.

The solid effervescent formulation is preferably intended to bemanufactured in compressed tablet form. Accordingly, when formulated asa tablet, the formulation will preferably consist of an admixture anddirect compression of a mixture of an internal phase consisting ofgranules and a powderous external phase. In a most preferred embodiment,the internal phase will comprise granules each containing a mixture ofthe antacid active ingredient, the corn starch bulking anddisintegrating agent, the effervescence base and the aroma agent. Inaccordance with this invention, the internal phase will be prepared bymixing and sieving the dry ingredients and wet granulating them withpurified water USP and sizing them with a sieve. The granules can thenbe admixed with a powderous blend of the external phase ingredients.

In a most preferred embodiment, the external phase will contain theeffervescence acid, one or more starch degrading enzymes, a tablettinglubricant, a sweetener and an aroma agent.

The admixture of internal and external phase ingredients can be directlycompressed in tablet form using conventional hydraulic punch equipment.The resulting tablet exhibits a smooth surface, stores well and issufficiently chip resistant to be easily packaged, shipped and handled.

Advantageously, the tablet will also be provided with a protective andflavoring coating consisting of polyols and flavoring agents, easilyknown by those skilled in the art. For example, a tablet made inaccordance with the present invention could be spray coated on top andbottom when passing on a sieve conveyor. For example, the polyolscoating could comprise a mixture of mannitol, purified water, propyleneglycol and xylitol and optional further flavoring agents. Colorants andother texture modifiers could also be added. The coated tablets exhibitfurther mechanical resistance for greater stability and improvedshelf-life.

Examples Of The Invention

The following example represents a most preferred embodiment of thepresent invention and is provided merely for illustrative purposes.

Example 1

Antacid tablets were prepared in accordance with the present invention.The tablets were formed by hydraulic punching of a mixture of sphericalgranules (internal phase) and a blend of powdered ingredients (externalphase). The formulation of the internal and external phases was asfollows:

    __________________________________________________________________________    INTERNAL PHASE                                                                                              weight % based                                                        weight %                                                                              on total weight of                                                    based on total                                                                        internal phase                                  ingredient                                                                              nature      tablet weight                                                                         ingredients only                                __________________________________________________________________________    calcium carbonate                                                                       active ingredient and                                                                     34.41   40.72                                                     effervescence base                                                  magnesium hydroxide                                                                     active ingredient                                                                         8.14    6.88                                            corn starch                                                                             swelling, disintegrating                                                                  47.43   40.08                                                     and salivation agent                                                sodium carbonate                                                                        effervescence base                                                                        3.71    3.13                                            peppermint oil                                                                          aroma                                                               W381025F                                                                      __________________________________________________________________________    EXTERNAL PHASE                                                                                              weight % based                                                        weight %                                                                              on total weight of                                                    based on total                                                                        external phase                                  ingredient                                                                              nature      tablet weight                                                                         ingredients only                                __________________________________________________________________________    talc      lubricant   14.71   2.35                                            malic acid                                                                              effervescence acid                                                                        24.82   3.97                                            enzyme, equal parts of                                                                  starch degradation                                                                        0.29    0.05                                            α-amytase and                                                                     agent                                                               amyloglucosidase                                                              peppermint aroma                                                                        aroma                                                               WL15,666                                                                      aspartame artificial sweetener                                                                      8.44    1.35                                            __________________________________________________________________________

In a Patterson Kelly, 8 pint, V-blender, the internal phase ingredientswere intimately mixed. This mixture was then wetted with purified waterUSP, dried and granulated in a fluidized-bed, Glatt CPGC-3 granulator.The resulting granules were then sieved to a substantially uniform sizerange of spherical granules. The granules were then admixed to a blendof the powdered external phase ingredients. The resulting mixture wasthen formed into tablets using a compression device such as aconventional hydraulic punch.

The tablets were sufficiently hard to resist chipping and breakageduring normal handling. However, when placed in the mouth, the tabletsrapidly collapsed and disintegrated with concomitant effervescence, i.e.in about 20 seconds, and left a pleasant minty, taste and freshness ofbreath.

The disintegration of the tablet was shown to increase salivation andfavor rapid ingestion of the active antacid ingredients.

Although the invention has been described above with respect to onespecific form, it will be evident to a person skilled in the art that itmay be modified and refined in various ways. It is therefore wished tohave it understood that the present invention should not be limited inscope, except by the terms of the following claims.

What is claimed is:
 1. A fast-melting solid dosage form destined foringestion and which will readily disintegrate when placed in the mouth,said solid dosage form comprising the following primary ingredients:(a)a therapeutically effective amount of a pharmaceutically acceptableactive ingredient component; (b) an effervescent couple consisting of aneffervescence base and an effervescence acid suitable for achieving agas evolving reaction with said effervescence based upon saideffervescent couple being contacted with an aqueous solution; (c) abulking and disintegrating agent consisting of starch; (d) at least onestarch degrading enzyme suitable for achieving a starch degradationreaction upon said solid dosage form being contacted with an aqueoussolution; (e) a solid dosage form lubricant.
 2. A solid dosage formaccording to claim 1 wherein said starch is present in a proportion of40 to 50 weight percent based on the total weight of said solid dosageform.
 3. A solid dosage form according to claim 1 wherein said starchdegrading enzyme is selected from the group of enzymes consisting ofα-amylase, β-amylase, amyloglucosidase, and glucose-fructose isomerase.4. A solid dosage form according to claim 2 wherein said starchdegrading enzyme is selected from the group of enzymes consisting ofα-amylase, β-amylase, amyloglucosidase, and glucose-fructose isomerase.5. A solid dosage form according to claim 3 wherein said starchdegrading enzyme is a mixture of amyloglucosidase and α-amylase.
 6. Afast-melting antacid tablet which will readily disintegrate when placedin the mouth, said antacid tablet comprising the following ingredientswhose proportions are calculated as weight percent on the total weightof the tablet:(a) an antacid component comprising about 33 weightpercent of calcium carbonate and about 6.5 weight percent of magnesiumhydroxide; (b) an effervescent couple consisting of about 3.5 weightpercent of sodium bicarbonate as an effervescence base and about 4weight percent of malic acid as an effervescence acid suitable forachieving a gas evolving reaction with said effervescence based uponsaid effervescent couple being contacted with an aqueous solution; (c) abulking and disintegrating agent consisting of corn starch in aproportion of about 40 weight percent; (d) a starch-degrading enzyme ina proportion of about 0.05 weight percent; and (e) a tablet lubricantconsisting of talc in a proportion of about 2.4 weight percent.
 7. Asolid dosage form according to claim 3 wherein the primary ingredientsare present in the following proportions calculated as weightpercentages of the total weight of the solid dosage form:(a) about 25 to50 weight percent, of a pharmaceutically acceptable active ingredient;(b) about 3 to 5 weight percent of an effervescence base and about 3 to5 weight percent of the effervescence acid; (c) about 35 to 50 weightpercent of the pharmaceutically acceptable starch; (d) about 0.04 to 2weight percent of the starch-degrading enzyme; (e) about 2 to 5 weightpercent of the lubricant.
 8. A solid dosage form according to claim 7wherein said solid dosage form is an antacid.
 9. A solid dosage formaccording to claim 8 wherein said solid dosage form is an antacidtablet.
 10. A solid dosage form according to claim 9 wherein said soliddosage form has an exterior coating comprising polyols so as to protectand impart a pleasant taste to said solid dosage form.
 11. An antacidtablet according to claim 9 wherein the starch is corn starch.
 12. Anantacid tablet according to claim 11 wherein said tablet comprising aninternal phase consisting of granules of a mixture of internal phaseingredients comprising as primary ingredients the antacid component, thecorn starch and the effervescence base, said internal phase ingredientsbeing in admixture and in direct compression with an external phasecomprising as primary ingredients the effervescence acid, the enzyme andthe tablet lubricant.
 13. The antacid tablet according to claim 12wherein said antacid active component consists of a mixture of about 30to 35 weight percent of calcium carbonate and about 6 to 7 weightpercent of magnesium hydroxide.
 14. The antacid tablet according toclaim 13 wherein said effervescence couple consists of sodiumbicarbonate as the effervescence base and malic acid as theeffervescence acid.
 15. The antacid tablet according to claim 14 whichadditionally includes an effective amount of a sweetening agent.
 16. Theantacid tablet according to claim 15 which additionally includes aneffective amount of at least one breath freshening agent.
 17. A methodfor treating gastric hyperacidity in humans comprising orallyadministering a therapeutically effective dosage of the tablet of claim6.
 18. A method for forming a tablet as defined in claim 1, said methodcomprising the steps of:(a) sieving to powder and mixing the primaryinternal phase ingredients, comprising the active ingredient component,the starch and the effervescence base to obtain an internal phasemixture; (b) wet granulating said mixture to obtain small granules; (c)sieving said granules to a generally uniform size distribution of saidgranules; (d) mixing said granules with the external phase primaryingredients comprising the effervescence acid, and the tablet lubricant;(e) compressing the resulting mixture in a compression device to obtaina porous and fast-melting antacid tablet.
 19. The method of claim 18wherein said external phase ingredients additionally comprise at leastone flavoring agent.
 20. The method of claim 18 wherein said antacidcomponent consists of a mixture of about 30 to 35 weight percent ofcalcium carbonate and about 6 to 7 weight percent of magnesiumhydroxide, said weight percentages being calculated on the total weightof the resulting tablet.
 21. A method for treating gastric hyperacidityin humans comprising orally administering a therapeutically effectivedosage of the solid dosage form of claim 6.